DOCSLIB.ORG

Successful Long-Term Treatment of Hyponatremia in Syndrome of Inappropriate Antidiuretic Hormone Secretion with Satavaptan (SR121463B), an Orally Active Nonpeptide

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Successful Long-Term Treatment of Hyponatremia in Syndrome of Inappropriate Antidiuretic Hormone Secretion with Satavaptan (SR121463B), an Orally Active Nonpeptide CJASN ePress. Published on October 11, 2006 as doi: 10.2215/CJN.00160106 Original Articles Successful Long-Term Treatment of Hyponatremia in Syndrome of Inappropriate Antidiuretic Hormone Secretion with Satavaptan (SR121463B), an Orally Active Nonpeptide Vasopressin V2-Receptor Antagonist ʈ Alain Soupart,*† Peter Gross,‡ Jean-Jacques Legros,§ Sa´ndor Alfo¨ldi, Djillali Annane,¶ Hassan M. Heshmati,†† and Guy Decaux† ** *Department of Internal Medicine, Jolimont/Tubize-Nivelles Hospital, Tubize, †Research Unit for the Study of Hydromineral Metabolism and **Department of General Internal Medicine, Erasmus University Hospital, Free University of Brussels, Brussels, and §Department of Internal Medicine, Regional Hospital Center of Citadelle, Liege, Belgium; ‡Nephrology, ʈ Department of Medicine, University Medical Center Care Gustav Carus, Dresden, Germany; Szent Imre Ko´rha´z e´s Rendelo¨inte´zet I, Belgyo´gya´szati Oszta´ly, Budapest, Hungary; ¶Department of Intensive Care Unit, Raymond Poincare Hospital, Garches, France; and ††Clinical Development, Sanofi-Aventis, Malvern, Pennsylvania The effects of satavaptan (SR121463B), a novel long-acting orally active vasopressin V2-receptor antagonist, were investigated in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In the first part of this randomized, double-blind study, 34 patients first were treated with satavaptan (versus placebo) for up to 5 d and then during 23 d of open-label dosage-adjustment period. In the second part of the study, long-term efficacy and safety of satavaptan was assessed in an open-label trial during at least 12 mo. Mean (؎SD) serum sodium (SNa) levels before treatment were 127 ؎ 2 mmol/L Responders (patients SNa levels .(12 ؍ and 127 ؎ 5 mmol/L (50 mg, n ,(14 ؍ mmol/L (25 mg, n 6 ؎ 125 ,(8 ؍ placebo, n) normalized or increased by at least 5 mmol/L from baseline during the double-blind period) were 79% in the 25-mg group (SNa ؎ and 13% in the placebo group (SNa 130 ,(0.005 ؍ in the 50-mg group (SNa 140 ؎ 6 mmol/L; P %83 ,(0.006 ؍ mmol/L; P 3 ؎ 136 5 mmol/L). No drug-related serious adverse events were recorded. During the long-term treatment, 15 of 18 enrolled patients achieved 6 mo and 10 achieved 12 mo of treatment. The SNa response was maintained during this time with a good tolerance. The new oral vasopressin V2-receptor antagonist satavaptan adequately corrects mild or moderate hyponatremia in patients with SIADH and has a good safety profile. Clin J Am Soc Nephrol 1: 634–640, 2006. doi: 10.2215/CJN.00160106 asopressin is involved in most cases of sustained hy- origins. After the initial phase of the study (short-term, 1 mo), ponatremia (1). Therefore, the use of specific blockers we evaluated for the first time the efficacy and the tolerance of of vasopressin receptors is a logical approach in the aVRA over a long-term period (12 mo). V 2 treatment of patients with syndrome of inappropriate antidi- uretic hormone secretion (SIADH) and may present advantages over current available therapies (2). Selective nonpeptide V - Materials and Methods 2 Patients receptor antagonists (V RA) have been in development since 2 From June 2001 to June 2003, a total of 35 patients from four countries 1992 (3–6). Oral compounds have been synthesized more re- (Belgium, Germany, Hungary, and France) were included in a random- cently, and, to our knowledge, publications have focused ized, double-blind, placebo-controlled study to assess the efficacy and mainly on patients with SIADH that is treated with an oral the safety of different dosages of satavaptan in SIADH. The diagnosis Ͻ V2RA for a short period of time ( 1 wk) (7–10). of SIADH was based on several criteria: True serum hypo-osmolality; In this study, we investigated the efficacy and the safety of a inappropriate urinary osmolality; clinical euvolemia; elevated urinary new oral nonpeptide V2RA, satavaptan (SR121463B) (11), in sodium excretion while on a normal salt and water intake; and normal correcting hyponatremia in patients with SIADH of various renal, adrenal, and thyroid functions. Patients with low sodium excre- tion (Յ20 mmol/L) as a result of low solute intake (anorexia) were included. Drug-induced SIADH was limited to carbamazepine and Received January 13, 2006. Accepted August 21, 2006. antidepressants. The search for the cause of SIADH (especially neopla- Published online ahead of print. Publication date available at www.cjasn.org. sia and iatrogenic) was performed carefully by each investigator before considering the origin as idiopathic. Address correspondence to: Dr. Alain Soupart, Research Unit for the Study of Inclusion criteria were age 18 yr or older, stable hyponatremia (se- Hydromineral Metabolism, Department of General Internal Medicine, Free Uni- Յ versity of Brussels, Hoˆpital Erasme, 808, route de Lennik, 1070 Brussels, Belgium. rum sodium [SNa] increase 4 mmol/L between two measurements of Phone: ϩ322-555-4960; Fax: ϩ322-555-3211; E-mail: [email protected] 24 h apart) between 115 and 132 mmol/L during the screening period, Copyright © 2006 by the American Society of Nephrology ISSN: 1555-9041/106-0634 Clin J Am Soc Nephrol 1: 634–640, 2006 Treatment of SIADH with Vasopressin V2RA 635 ability to give a written informed consent, and ability to follow verbal chromatography tandem mass spectrometry (Department of Sanofi- and written instructions. Exclusion criteria were cardiac failure, symp- Synthelabo Research, Malvern, PA). Urine samples were collected daily tomatic liver disease or serum alanine aminotransferase or aspartate (collections from 8 a.m. to 2 p.m., and from 2 p.m. to 8 a.m.) for urinary aminotransferase more than two-fold the upper limit of normal, un- volume, electrolyte, and osmolality determinations. controlled diabetes (blood glucose Ն200 mg/dl), significant renal im- Free water clearance (FWC) was calculated using the following for- pairment (serum creatinine Ͼ150 ␮mol/L), inadequate hematologic mula: (urinary flow rate) ϫ (1 Ϫ urinary osmolality/serum osmolality). function (hemoglobin Ͻ9 g/dl, neutrophils Ͻ1500/mm3, platelets Effective FWC (EFWC) was calculated using the following formula: Ͻ100,000/mm3), and hypothyroidism or adrenal deficiency. Radiother- (urinary flow rate) ϫ (1 Ϫ urinary sodium ϩ potassium/SNa). apy and chemotherapy within 2 wk before study drug administration Written informed consent was obtained from each patient. The study were not allowed. Previous and concomitant administration of some protocol was approved by the local ethics committee of the participat- drugs were not accepted (from 1 mo before the randomization for ing centers. demeclocycline or lithium and 2 d for diuretics and urea). Women who were of childbearing potential and had positive pregnancy test and Statistical Analyses women with absence of medically approved contraceptive methods Data are provided as mean Ϯ SD or SEM as appropriate. All statis- were excluded. tical tests were two sided at the 5% significance level. Comparison of data between treatment groups was done by using ANOVA for con- Protocol tinuous data and Fisher exact test for qualitative variables. In the first part of the study (1 mo), after a screening period (day Ϫ6 to day Ϫ1) to confirm stable hyponatremia, patients were randomly assigned to take placebo or a once-daily dose of 25 or 50 mg of Results satavaptan during a double-blind period of up to 5 d. The duration of Short-Term Study (First Part) the double-blind period could have been Ͻ5 d if SNa reached values In the double-blind phase, nine patients received placebo, 14 Ն135 mmol/L on two consecutive days before day 5. Patients were patients received 25 mg/d, and 12 patients received 50 mg/d of hospitalized during the double-blind period. The double-blind period satavaptan. Thirty-four patients completed the double-blind was followed by 23 d of open-label treatment (dosage adjustment). In portion of the study. One patient in the placebo group discon- the initial dosage adjustment on day 6, if the last SNa on day 5 was tinued the treatment on the second day because of an adverse Ͻ135 mmol/L, then patients received a dosage of satavaptan equal to event. Twenty-two patients completed the open-label portion Ն the dosage of their group. If SNa was 135 mmol/L, then they received of the study. Thirteen patients discontinued the open-label a dosage that was one level below the dosage of their group (in case of period for various reasons (e.g., adverse event, death, lack of 25 mg, the drug was discontinued). From day 7 to the end of the efficacy, personal reason). open-label period, the dosage was adjusted on the basis of the results of There were no significant differences in the baseline charac- SNa. In the second part of the study (12 mo), the long-term efficacy and the safety of the satavaptan were assessed in an open-label trial with teristics of the patients between groups (Table 1). In the patients 12.5, 25, or 50 mg once daily. with drug-induced SIADH, all cases were related to carbamaz- Drug was administered in the morning under fasting conditions. epine that was prescribed for epilepsy or chronic pain (the drug During the entire study, it was recommended to limit total fluid intake was continued during the study). Patients presented with mod- to 1500 ml/d. Dietary sodium intake remained unchanged throughout erate hyponatremia (range 114 to 131 mmol/L). The low uri- the study for each patient. nary sodium that was observed in some patients may be attrib- Treatment aim was to obtain normalization of the SNa within a range uted to the low caloric and solute intake of the patients. of 135 to 145 mmol/L on two separate consecutive determinations. Efficacy. Figure 1 represents the course of the SNa Responders were patients who reached normal SNa levels or increasing throughout the double-blind period.
Load more

Recommended publications
  • Article Efficacy and Tolerance of Urea Compared with Vaptans for Long
    Article Efficacy and Tolerance of Urea Compared with Vaptans for Long-Term Treatment of Patients with SIADH Alain Soupart,*† Michel Coffernils,* Bruno Couturier,† Fabrice Gankam-Kengne,† and Guy Decaux† Summary Background and objectives Vaptans (vasopressin V2-receptor antagonists) are a new approach for the treatment of hyponatremia. However, their indications remain to be determined, and their benefit compared with that of the usual treatments for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) have not been *Department of fi Internal Medicine, evaluated. This prospective, long-term study compared the ef cacy, tolerability, and safety of two oral vaptans Jolimont/Tubize with those of oral urea in patients with SIADH. Hospital, Tubize, Brabant, Belgium; and † Design, setting, participants, & measurements Patients with chronic SIADH of various origins were treated first Research Unit for the Study of Hydromineral with vaptans for 1 year. After an 8-day holiday period, they received oral urea for an additional 1-year follow-up. Metabolism, Serum sodium was measured every 2 months, and drug doses were adjusted accordingly. Department of General Internal Results Thirteen participants were initially included in the study (serum sodium, 12563 mEq/L); 12 completed Medicine, Erasmus the 2-year treatment period. Treatment with vaptans (satavaptan, 5–50 mg/d, n=10; tolvaptan, 30–60 mg/day, University Hospital, Brussels, Belgium n=2) increased natremia (serum sodium, 13563 mEq/L) during the 1-year vaptan period without escape. Hyponatremia recurred in the 12 participants when vaptans were stopped (holiday period). Urea improved the Correspondence: natremia with the same efficacy (serum sodium, 13562 mEq/L) as vaptans during the 1-year urea treatment Dr.
    [Show full text]
  • Hypernatremia: 2 Months Back When He Had Progressive Decrease in Vision (Right > Left)
    Correspondence to increased intrathoracic pressure and central radiologist regarding vascular injury when there is venous pressure, decreased venous return from the refractory hypotension so that necessary steps can be brain and increased ICP[4] taken to identify and treat iatrogenic complications that • Patients with aneurysmal SAH have disturbed might compound the pre‑existing morbidity. autoregulation of cerebral blood flow. Hence, intraoperative hypotension of any cause has an REFERENCES adverse effect on the outcome of SAH[5,6] • Patients with poor grade SAH (Fischer III/IV) and 1. Young WL, Pile-Spellman J. Anesthetic considerations for interventional Neuroradiolgy (Review). Anesthesiology angiographic evidence of vasospasm which our 1994;80:427-56. patient had, are at risk for cerebral hypoperfusion 2. Varma MK, Price K, Jayakrishnan V, Manickam B, Kessell G. because of impaired cerebral autoregulation and Anaesthetic considerations for interventional neuroradiology. thus intraoperative hypotension and cerebral Br J Anaesth 2007;99:75-85. [6,7] 3. Kent KC, Moscucci M, Mansour KA, Dimattia S, Gallagher S, hypoperfusion compounds the poor outcome Kuntz R, et al. Retroperitoneal hematoma after cardiac • Blood loss leading to severe anaemia (Hb 3.8 g%) catheterization: Prevalence, risk factors, and optimal during the procedure might have lead to decreased management. J Vasc Surg 1994;20:905-10. oxygen‑carrying capacity of blood and further 4. De Laet I, Citerio G, Malbrain ML. The influence of exacerbate the hypoxic injury to brain. intraabdominal hypertension on the central nervous system: Current insights and clinical recommendations, is it all in the Thus a combination of age, poor grade SAH, diffuse head? Acta Clin Belg Suppl 2007;1:89-97.
    [Show full text]
  • Vaptans and the Treatment of Water-Retaining Disorders Friedericke Quittnat and Peter Gross
    Vaptans and the Treatment of Water-Retaining Disorders Friedericke Quittnat and Peter Gross Hyponatremia is a frequent and symptomatic electrolyte disorder for which specific treat- ments have been lacking. Hyponatremia is attributable to nonosmotic vasopressin stimu- lation and continued increased fluid intake. In the past, peptidic derivatives of arginine vasopressin proved that blockade of vasopressin V-2 receptors served to improve hypo- natremia, however, these antagonists had intrinsic agonistic activity, too. In the past decade, random screening of molecules uncovered nonpeptide, orally available vasopres- sin antagonists without agonistic properties. The agents show competitive binding to the vasopressin V-2 receptor at an affinity comparable with that of arginine vasopressin. Four antagonists have undergone extensive study. Three of these agents—lixivaptan or VPA 985; SR 121 463 B; tolvaptan or OPC 41,061—are specific V-2 antagonists whereas conivaptan or YM 087 is a V-1/V-2 mixed antagonist. In animal and clinical studies all of the agents were able to correct water retention and hyponatremia in a dose-dependent manner. There was no tachyphylaxis, even when the agents were given over many weeks. It is expected that the clinical use of the agents will lead to a major improvement in the treatment of hyponatremia. Semin Nephrol 26:234-243 © 2006 Elsevier Inc. All rights reserved. KEYWORDS hyponatremia, vasopressin, vaptans, cardiac failure, syndrome of inappropriate antidiuretic hormone (SIADH) yponatremia is a water-retaining disorder that is de- in outpatients, especially when older patients are consid- Hfined by the presence of a plasma sodium concentration ered.3 of 136 mmol/L or less.
    [Show full text]
  • The Structure and Function of V1b Vasopressin Receptor
    The Structure and Function of V1b Vasopressin Receptors Yukie Goto A thesis submitted to the University of Birmingham for the degree of Doctor of Philosophy School of Biosciences University of Birmingham Edgbaston, Birmingham B15 2TT, United Kingdom September 2009 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Acknowledgement Firstly I would like to thank my supervisor Professor Mark Wheatley for giving me this opportunity to participate in his research, and for his support and guidance throughout my study. I would also like to thank those who have worked in his research group: in particular John for providing us with molecular models of vasopressin receptors; Alex, Mattew, Denise, Cymone and Amelia, for equipping me with the laboratory techniques required for carrying out this study; and Rachel and Richard for their companies and supports in the research group for last few years. I am truly grateful to Dr. David Poyner and Prof. Ian Martin for their inspiring teachings on this subject area in my undergraduate years. My gratitude goes to Rosemary for her conscientious hard work in looking after laboratories, equipments, and students; and to Eva, David, Karthik, Prof.
    [Show full text]
  • Management of Hyponatremia
    E CMAJ M Review C Management of hyponatremia Jennifer Ji Young Lee BHSc, Kajiru Kilonzo MD, Amy Nistico MD, Karen Yeates MD yponatremia, defined as a decrease in How does the type of Competing interests: serum sodium below 136 mmol/L, is a Karen Yeates has received hyponatremia affect treatment? honoraria for a career H common occurrence in both inpatients mentorship talk from and outpatients and can be found in up to 15% Amgen and for a continuing of the general hospital populations. 1,2 Acute Although there are many approaches to the man - medical education event from Otsuka hyponatremia (duration < 48 h) and its manage - agement of hyponatremia, one of the most com - Pharmaceuticals. No other ment can be a cause of major morbidity and mon approaches used by nonexpert clinicians competing interests were mortality among patients in hospital. 3 Chronic begins with an assessment of extracellular fluid declared. hyponatremia (duration > 48 h), which is typi - (ECF) volume status. Because diabetes mellitus This article has been peer cally seen among older ( ≥ 65 yr) outpatients, is becoming more prevalent in the adult popula - reviewed. also contributes to morbidity because it is often tion, clinicians should be mindful of ruling out Correspondence to: unrecognized. 3,4 Typically, correction of serum hyperosmolar hyponatremia caused by hyper - Karen Yeates, sodium concentration in patients with acute glycemia as a potential cause of hyponatremia. [email protected] hyponatremia should occur at a more rapid rate The clinical history and physical examination CMAJ 2014. DOI:10.1503 than in patients with chronic hyponatremia provide important diagnostic clues that help to /cmaj.120887 because the symptoms are usually more severe classify the cause of hyponatremia as hypov - when serum sodium rapidly decreases over a olemic, euvolemic or hypervolemic.
    [Show full text]
  • Utility and Safety of Tolvaptan in Cirrhotic Patients with Hyponatremia: a Prospective Cohort Study
    Tolvaptan in cirrhosis. , 2017; 16 (1): 123-132 123 ORIGINAL ARTICLE January-February, Vol. 16 No. 1, 2017: 123-132 The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver Utility and Safety of Tolvaptan in Cirrhotic Patients with Hyponatremia: a Prospective Cohort Study Ji-Dong Jia,1 Wen Xie,2 Hui-Guo Ding,3 Hua Mao,4 Hui Guo,5 Yonggang Li,6 Xiaojin Wang,7 Jie-Fei Wang,8 Wei Lu,9 Cheng-Zhong Li,10 Yimin Mao,11 Gui-Qiang Wang,12 Yue-qiu Gao,13 Bangmao Wang,14 Qin Zhang,15 Yan Ge,16 Vincent Wai-Sun Wong17,18 1 Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China. 2 Beijing Di Tan Hospital, Capital Medical University, Beijing, China. 3 Department of Gastroenterology and Hepatology, Beijing You’an Hospital affiliated with Capital Medical University, Beijing, China. 4 Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, China. 5 First Teaching Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, China. 6 Department of Integrative Medical Center, 302 Military Hospital of People’s Liberation Army, Beijing, China. 7 Hospital 85 People’s Liberation Army of China, Shanghai, China. 8 Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai, China. 9 Tianjin Second People-s Hospital, Tianjin First Center Hospital, Tianjin, China. 10 Changhai Hospital, The Second Military Medical University, Shanghai, China. 11 Renji Hospital Shanghai, Jiao Tong University School of Medicine, Shanghai, China. 12 Peking University First Hospital, Beijing, China.
    [Show full text]
  • Download Download
    Medical Research Archives. Vol. 5 Issue 1.January 2017. THE USE OF VASOPRESSIN RECEPTOR ANTAGONISTS IN HYPONATREMIA Authors: ABSTRACT ShraddhaRana MD, Hyponatremia is one of the most common ApurvKhanna, MD electrolyte disorder seen in hospitalized patients which is independently associated with Authors Note: increased mortality and in some series with Division of Nephrology, Department of increased length of hospital stay. Hyponatremia Medicine, SUNY Upstate Medical University, is also recognized as a poor prognostic indicator Syracuse, NY in certain subgroup of patients. The current available modalities used in treating euvolemic Corresponding Author: and hypervolemic hyponatremia are at times ApurvKhanna, MD ineffective and unable to address the underlying 343 CWB pathophysiology of ADH excess. Vasopressin 750 E Adams Street also known as Anti Diuretic hormone acting Syracuse, NY, 13210 throughV2 receptor is the primary physiologic USA determinant of the rate of free water excretion. Phone: 1-315-464-5290 This class of drugs holds a physiologic Fax: 1-315-464-5295 advantage over the current and commonly used Email: [email protected] agents in treating hyponatremia.In the last decade, knowledge of vasopressin receptors has increased significantly.Multiple vasopressin receptor antagonists have been developed with differences in their specificity to V2:V1 receptors. These agents have applications in conditions of hypervolemic and euvolemic hyponatremia such as syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, cirrhosis and perhaps in brain edema following traumatic brain injury. Although V2 receptor antagonist may have clear proven role in correcting hyponatremia in certain condition, its use continues to remain limited. Various factors but mainly its lack of association with decrease in mortalityand high cost has prevented its widespread use.
    [Show full text]
  • Vaptans and Hyponatremia in Critical Patients
    Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14 VAPTANS AND HYPONATREMIA IN CRITICAL PATIENTS David D’Auria, Geremia Zito Marinosciˡ, Giuseppe De Benedictis, Ornella Piazza² 1 Department of Anesthesia and Intensive Care, Federico II University, Napoli, Italy ² Department of Medicine, University of Salerno, Salerno, Italy ABSTRACT: Hyponatremia is the most frequent manifestation depend on many factors (time of duration, fluid and electrolyte disorder in hospitalized patients velocity of sodium decrease, sodium levels, patients age, (20%), particularly in ICU, associated with an increase comorbidities) (3) and can give few and aspecific signs in morbility and mortality. While hypovolaemic and symptoms (fatigue, anorexia, nausea, behavioral hyponatremia needs to be corrected with the alterations) when sodium level is higher than 125 mEq/l or replacement of the lost extracellular fluid by isotonic the hyponatremia is chronic or it may cause more serious saline, euvolaemic (SIADH) and hypervolaemic derangements when sodium level is below 120 mEq/l or hyponatremia (oedematous states like decompensated hyponatremia is acute (cerebral edema, encephalopathy, heart failure, liver cirrhosis, i.e.) are treated by seizures, coma) (3, 4). Nevertheless, hyponatremia is a restriction of fluid intake, loop diuretics and predictor of poor outcomes in patients with heart failure. hypertonic saline. A novel approach consists in use of Patients with heart failure and hyponatremia often have vaptans, non-peptide arginine vasopressin (AVP) inappropriately elevated plasma vasopressin levels and receptor antagonists. Vaptans cause “aquaresis”, significantly poorer long-term prognosis than those with which results in the correction of plasma osmolality heart failure and normal serum sodium levels. (5) and serum sodium levels, without activation of the renin-angiotensin-aldosterone system or changes in With regard to the osmolality, except for a few cases of blood pressure and renal function.
    [Show full text]
  • The Treatment of Vasopressin V2-Receptor Antagonists in Cirrhosis Patients with Ascites
    Yan et al. BMC Gastroenterology (2015) 15:65 DOI 10.1186/s12876-015-0297-z RESEARCH ARTICLE Open Access The treatment of vasopressin V2-receptor antagonists in cirrhosis patients with ascites: a meta-analysis of randomized controlled trials Long Yan1†, Feng Xie1†, Jiongjiong Lu1, Qingqiang Ni1, Changying Shi1, Caixi Tang2 and Jiamei Yang1* Abstract Background: Ascites is the most common complication of cirrhosis. It may lead to the consequence of poor prognosis and the deterioration of quality of life. Asopressin V2 receptor antagonists is a kind of vaptans, and it has been proved to be effective in hyponatremia patients. We conducted a meta-analysis about treatment of vaptans in cirrhosis patients with ascites. Methods: Following our selection criteria, we collected a total of 14 studies containing 16 randomized controlled trials (2620 patients) from a series of database about the treatment with vaptans for cirrhosis with ascites patients. The included studies compared the treatment effect of lixivaptan (VPA 985), or RMJ-351647, or satavaptan, or tolvaptan with placebo. Results: The included vaptans (asopressin V2 receptor antagonists) showed significant effect of increasing the serum sodium concentration for cirrhosis patients (WMD = 2.11 mmol/L, p < 0.00001). Patients also could acquire significant improvement of ascites, as this kind of aquaretics can significantly reduce ascites patients’ weight (WMD = −1.53, p < 0.00001), abdominal girth (WMD = −2.04, p < 0.00001), and the ratio of worsening ascites (RR = 0.51, p = 0.001). Though the drug did not produce more total adverse events (RR = 1.04, p = 0.09) and the total serious events (RR = 1.04, p = 0.42), the emergence of excessive correction of serum sodium concentrations (>145 mmol/L) was more frequently noted in patients under the employment of vaptans (RR = 2.14, 95 % CI [1.45, 3.16], p = 0.0001).
    [Show full text]
  • Assessment Report on the Withdrawal of the Marketing Application
    European Medicines Agency Pre-authorisation Evaluation of Medicines for Human Use London, 26 June 2008 Doc. Ref: EMEA/CHMP/316130/2008 WITHDRAWAL ASSESSMENT REPORT FOR AQUILDA International Nonproprietary Name: satavaptan Procedure No. EMEA/H/C/873 Day 120 Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. This should be read in conjunction with the “Question and Answer” document on the withdrawal of the application: the Assessment Report may not include all available information on the product if the CHMP assessment of the latest submitted information was still ongoing at the time of the withdrawal of the appli- cation. 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 13 E-mail: [email protected]. http://www.emea.europa.eu © European Medicines Agency, 2008. Reproduction is authorised provided the source is acknowledged TABLE OF CONTENTS I. RECOMMENDATION............................................................................................................. 3 II. EXECUTIVE SUMMARY........................................................................................................ 3 II.1 Problem statement..................................................................................................................... 3 II.2 About the product ..................................................................................................................... 4 II.3 The development programme/Compliance with CHMP Guidance/Scientific
    [Show full text]
  • Vasopressin Antagonists in the Treatment of Water-Retaining Disorders
    Vasopressin Antagonists in the Treatment of Water-Retaining Disorders Sumit Kumar, MD, MPH,* and Tomas † Berl, MD Summary: The tools available to physicians for the treatment of hyponatremia, the most common of electrolyte disorders, are limited by lack of effectiveness, compliance difficulties, and toxicity problems. For this reason the development of novel oral antagonists of vasopressin provide a new approach to the management of these disorders. Since vasopressin plays a central role in the pathogenesis of most hyponatremic disorders, the inhibition of binding of the hormone to its receptors is likely to provide a most reliable and reproducible response leading to increases in free water excretion. This article reviews many of the studies that have been undertaken with this new class of agents, both in hypovolemic and hypervolemic settings. Semin Nephrol 28:279-288 © 2008 Elsevier Inc. All rights reserved. Keywords: Vasopressin, antagonists, hyponatremia, treatment yponatremia is perhaps the most com-VASOPRESSIN PHYSIOLOGY monly occurring electrolyte disorder in Hhospitalized patients.1 Although mild Vasopressin’s primary site of action is the hyponatremia (serum sodium level, 130-134principal cell of the renal collecting tubules, mEq/L) is very common, occurring in 15%where to the V2 receptors (V2R) predominantly 20% of hospitalized patients,2 it often is asymp-are expressed, although minor expression is tomatic. More severe hyponatremia (serum knownso- in the vascular endothelium where dium level,Ͻ 125 mEq/L) with possibly seriousthey stimulate the release of von Willebrand consequences occurs less commonly.3,4 The most factor and factor 8. The V2R is part of a common causes of hyponatremia are the broadersyn- family ofs -protein– G coupled recep- drome of inappropriate antidiuretic hormonetors that differ in localization and action.
    [Show full text]
  • Lixivaptan: a Vasopressin Receptor Antagonist for the Treatment of Hyponatremia
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector commentary promotes angiogenesis in normocholes- 9. Vasquez-Vivar J, Kalyanaraman B, Martasek P zed their serum sodium levels as com- terolemic animals. Nat Med 2000; 6: et al. Superoxide generation by endothelial 4,5 1004–1010. nitric oxide synthase: the influence of pared with placebo. Data also demon- 8. Guzik TJ, Mussa S, Gastaldi D et al. cofactors. Proc Natl Acad Sci USA 1998; 95: strate the long-term safety and efficacy Mechanisms of increased vascular superoxide 9220–9225. (out to approximately 2 years) of production in human diabetes mellitus: role 10. Tsutsui M, Milstien S, Katusic ZS. Effect of 6 of NAD(P)H oxidase and endothelial nitric tetrahydrobiopterin on endothelial function tolvaptan. The ability to specifically oxide synthase. Circulation 2002; 105: in canine middle cerebral arteries. Circ Res target arginine vasopressin provided a 1656–1662. 1996; 79: 336–342. physiologically based therapy for hypo- natremia that was safe and reliable. In two articles in this issue of Kidney see original articles on page 1215 and 1223 International, Abraham and colleagues report on the effects of a new oral, Lixivaptan: a vasopressin receptor non-peptide vasopressin V2 receptor, lixivaptan, in the treatment of both in- antagonist for the treatment of and outpatients with euvolemic hypo- natremia.7,8 The studies, LIBRA and hyponatremia HARMONY, differ in that the former trial required initial titration of Mitchell H. Rosner1 lixivaptan in the inpatient setting, whereas, in the latter trial, lixivaptan was Hyponatremia, the most common electrolyte disorder encountered in initiated in the outpatient setting (Table 2 clinical practice, is associated with significant morbidity and mortality.
    [Show full text]